Timo Strunker

• Prof. Dr.
• Head of Molecular Reproductive Physiology at University of Münster

STUDY QUESTION Do the main psychoactive phytocannabinoid delta-9-tetrahydrocannabinol (THC) and its non-psychoactive analog cannabidiol (CBD) affect human sperm function? SUMMARY ANSWER THC and CBD affect the sperm-specific Ca2+ channel CatSper, suppress activation of the channel by progesterone (P4) and prostaglandin E1 (PGE1), and THC also alter...

Background and Purpose Loss of function of the sperm‐specific Ca²⁺ channel CatSper is a common channelopathy that causes male infertility. CatSper controls the intracellular Ca²⁺ concentration and, thereby, the motility of human sperm. Activation of CatSper by oviductal ligands evokes a transient Ca²⁺ increase, which entails changes in the flagella...

Sperm activation is controlled by an influx of calcium ions through the CatSper channel, which is activated in the oviduct by a non-genomic action of progesterone. Progesterone has been hypothesized to act as an activator of ABHD2 activity, which in turn hydrolyses 1- and 2- arachadinoyl glycerol, putative inhibitors of CatSper. To explore the idea...

To locate and fertilize the egg, sperm probe the varying microenvironment prevailing at different stages during their journey across the female genital tract. To this end, they are equipped with a unique repertoire of mostly sperm-specific proteins. In particular, the flagellar Ca²⁺ channel CatSper has come into focus as a polymodal sensor used by...

This article discusses the extensive use of publication counts as indicators of trends in the scientific activities of individual researchers, research groups, and entire disciplines. However, with the growing number of articles in general, these counts might produce false impressions among scientists. We propose a straightforward yet effective nor...

UNSTRUCTURED This article discusses the extensive use of publication counts as indicators of trends in the scientific activities of individual researchers, research groups, and entire disciplines. However, with the growing number of articles in general, these counts might produce false impressions among scientists. We propose a straightforward yet...

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of me...

Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 ( Cylc1/CYLC1 ) and the autosomal Cylicin 2 ( Cylc2/CYLC2 ) genes, have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While...

Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cyli...

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson’s, Alzheimer’s, schizophrenia, and drug addiction. The development of selectiv...

Study question Is a loss of CatSper function in sperm a common cause of unexplained male infertility? Summary answer Loss of CatSper function leads to similar infertility phenotypes in mice and men and represents one of the most common causes of unexplained male infertility. What is known already Male infertility is often due to low sperm counts,...

The infertility of many couples seems to rest on an enigmatic dysfunction of the men's sperm, rendering early diagnosis and evidence-based treatment by medically assisted reproduction impossible. Using a novel laboratory test, we assessed the function of the flagellar calcium channel CatSper in sperm of almost 2,300 men undergoing a fertility worku...

Cylicins are testis specific proteins which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylic...

Cylicins are testis specific proteins which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylic...

N-Acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) is the major enzyme for the biosynthesis of the endocannabinoid anandamide. The role of NAPE-PLD in various physiological and pathophysiological conditions is currently under investigation. For example, the enzyme might be involved in the control of neuronal activity, embryonic...

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder affecting the function of motile cilia in several organ systems. In PCD, male infertility is caused by defective sperm flagella composition or deficient motile cilia function in the efferent ducts of the male reproductive system. Different PCD-associated genes encoding axonemal components...

The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a known regulator of membrane protein trafficking. PI(3,5)P2 facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. F...

Cylicins are testis specific proteins which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylic...

The sperm-specific Ca2+ channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration and, thereby, the swimming behavior of sperm from many species. The steroidal ethylenediamine RU1968 (1) represents a well-characterized, potent, and fairly selective cross-species inhibitor of CatSper. Due to its two additional centers o...

N-methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR is associated with diseases like Alzheimer’s, Huntington’s, depression and substance addiction. The development of select...

1,2-Diacylglycerol lipases (DAGL) are the most important enzymes for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG), and their role in various pathophysiological conditions is currently under investigation. We synthesized a new 1,2-diacylglycerol substrate for these enzymes with a fluorogenic 4-(pyren-1-yl)butanoyl residue in...

Fluorescent probes that change their spectral properties upon binding to small biomolecules, ions, or changes in the membrane potential (V m) are invaluable tools to study cellular signaling pathways. Here, we introduce a novel technique for simultaneous recording of multiple probes at millisecond time resolution: frequency-and spectrally-tuned mul...

STUDY QUESTION Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm? SUMMARY ANSWER The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro. WHAT IS KNOWN ALREADY In human sperm, CatSper translates changes of the chem...

Study question Do Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants affect the function of human sperm? Summary answer The SSRI-antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro. What is known already In human sperm, CatSper translates changes of the chem...

The sperm-specific Ca2+ channel CatSper registers chemical cues that assist human sperm to fertilize the egg. Prime examples are progesterone and prostaglandin E1 that activate CatSper without involving classical nuclear and G protein-coupled receptors, respectively. Here, we study the action of seminal and follicular fluid as well of the contained...

The reaction of CO 2 with H 2 O to form HCO 3 ⁻ and H ⁺ is one of the most important chemical equilibria in cells. In mammalian sperm, a soluble adenylyl cyclase (sAC) serves as cellular HCO 3 ⁻ sensor that conveys the equilibrium state via cAMP synthesis to cAMP-signaling molecules. The function of sAC and cAMP in non-mammalian sperm is largely un...

Motile cilia line the efferent ducts of the mammalian male reproductive tract. Several recent mouse studies have demonstrated that a reduced generation of multiple motile cilia in efferent ducts is associated with obstructive oligozoospermia and fertility issues. However, the sole impact of efferent duct cilia dysmotility on male infertility has no...

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that pre...

Mammalian oocytes are enveloped by the zona pellucida (ZP), an extracellular matrix of glycoproteins. In sperm, stimulation with ZP proteins evokes a rapid Ca²⁺ influx via the sperm-specific, pH-sensitive Ca²⁺ channel CatSper. However, the physiological role and molecular mechanisms underlying ZP-dependent activation of CatSper are unknown. Here, w...

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The sperm-specific CatSper channel controls the influx of Ca2+ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activ...

Background/aims: The cardiac current IKs is carried by the KCNQ1/KCNE1-channel complex. Genetic aberrations that affect the activity of KCNQ1/KCNE1 can lead to the Long QT Syndrome 1 and 5 and, thereby, to a predisposition to sudden cardiac death. This might be prevented by pharmacological modulation of KCNQ1/KCNE1. The prototypic KCNQ1/KCNE1 acti...

The sperm-specific CatSper channel controls the influx of Ca ²⁺ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing acti...

Navigation of sperm in fluid flow, called rheotaxis, provides long-range guidance in the mammalian oviduct. The rotation of sperm around their longitudinal axis (rolling) promotes rheotaxis. Whether sperm rolling and rheotaxis require calcium (Ca 2+) influx via the sperm-specific Ca 2+ channel CatSper, or rather represent passive biomechanical and...

Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca2+ rise that controls motility. The mechanisms underlying such ultra-sensitivity are ill-defined. Here, we determine by mass spectrometry the copy number of nineteen chemosensory...

Inside the female genital tract, mammalian sperm undergo a maturation process called capacitation, which primes the sperm to navigate across the oviduct and fertilize the egg. Sperm capacitation and motility are controlled by 3′,5′-cyclic adenosine monophosphate (cAMP). Here, we show that optogenetics, the control of cellular signaling by genetical...

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This h...

The Cysteine-RIch Secretory Proteins (CRISPs) are a group of proteins which show a pronounced expression biased to the male reproductive tract. While sperm encounter CRISPs at virtually all phases of sperm development and maturation, CRISP2 is the sole CRISP produced during spermatogenesis, wherein it is incorporated into the developing sperm head...

Sperm from sea urchins are attracted by chemical cues released by the egg—a mechanism called chemotaxis. We describe here the signaling pathway and molecular components endowing sperm with single-molecule sensitivity. Chemotactic signaling and behavioral responses occur on a timescale of a few milliseconds to seconds. We describe the techniques and...

Study question: Does the chemosensory activation of CatSper Ca2+ channels in human sperm give rise to additive, sub-additive or even synergistic actions among agonists? Summary answer: We show that oviductal ligands and endocrine disrupting chemicals (EDCs) activate human CatSper highly synergistically. What is known already: In human sperm, t...

Voltage-sensing (VSD) and cyclic nucleotide-binding domains (CNBD) gate ion channels for rapid electrical signaling. By contrast, solute carriers (SLCs) that passively redistribute sub-strates are gated by their substrates themselves. Here, we study the orphan sperm-specific solute carriers SLC9C1 that feature a unique tripartite structure: an exch...

Background and purpose: Sperm from many species share the sperm-specific Ca2+ channel CatSper (cation channel of sperm) that controls the intracellular Ca2+ concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling CatSper activity and the role of the channel during fertilization differ...

Grant: This work was supported by German Research Foundation Grants CRU326 (to T.S. and F.T.) and SFB1089 (to U.B.K.); Cells-in- Motion Cluster of Excellence (Münster) Grant CiM20027 (to T.S.); and a research fellowship from the European Society for Paediatric Endocrinology (to I.V.W.).

Background/aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treat...

Key points: In human sperm, proton flux across the membrane is controlled by the voltage-gated proton channel Hv1. We show that sperm harbour both Hv1 and an N-terminally cleaved isoform termed Hv1Sper. The pH-control of Hv1Sper and Hv1 is distinctively different. Hv1Sper and Hv1 can form heterodimers that combine features of both constituents. Cl...

For a given sensory cell type, signaling motifs are rather uniform across phyla. By contrast, sperm from different species use diverse repertoires of sperm-specific signaling molecules and even closely related protein isoforms feature different properties and serve different functions. This surprising diversity has consequences for strategies in fe...

Characteristics of mlCNBD-FRET.Binding affinities and the cerulean lifetime are shown as mean ± S.D.; n numbers are indicated.DOI: http://dx.doi.org/10.7554/eLife.14052.010

Characteristics of other cAMP biosensors.DOI: http://dx.doi.org/10.7554/eLife.14052.011

Fertility parameters of mlCNBD-FRET transgenic males.For matings, heterozygous males have been crossed with wild-type females. All data are represented as mean ± S.D., n numbers are indicated.DOI: http://dx.doi.org/10.7554/eLife.14052.008

ELife digest Cells can change the way they grow, move or develop in response to information from their environment. This information is first detected at the surface of the cell and then the information is relayed around the interior of the cell by signaling molecules known as “second messengers”. A molecule called cAMP is a well-known second messe...

Many cells probe their environment for chemical cues. Some cells respond to picomolar concentrations of neuropeptides, hormones, pheromones, or chemoattractants. At such low concentrations, cells encounter only a few molecules. The mechanistic underpinnings of single-molecule sensitivity are not known for any eukaryotic cell. Sea urchin sperm offer...

The Prm1-bPAC mouse model shows no change in fertility parameters.Data are given as mean ± s.d.; n = number of experiments.DOI: http://dx.doi.org/10.7554/eLife.05161.004

Sperm guidance is controlled by chemical and physical cues. In many species, Ca(2+) bursts in the flagellum govern navigation to the egg. In Arbacia punctulata, a model system of sperm chemotaxis, a cGMP signaling pathway controls these Ca(2+) bursts. The underlying Ca(2+) channel and its mechanisms of activation are unknown. Here, we identify CatS...

Guanylyl cyclases (GCs), which synthesize the messenger cyclic guanosine 3',5'-monophosphate, control several sensory functions, such as phototransduction, chemosensation, and thermosensation, in many species from worms to mammals. The GC chemoreceptor in sea urchin sperm can decode chemoattractant concentrations with single-molecule sensitivity. T...

Synthetic endocrine disrupting chemicals (EDCs), omnipresent in food, household, and personal care products, have been implicated in adverse trends in human reproduction, including infertility and increasing demand for assisted reproduction. Here, we study the action of 96 ubiquitous EDCs on human sperm. We show that structurally diverse EDCs activ...

Synthetic endocrine disrupting chemicals (EDCs), omnipresent in food, household, and personal care products, have been implicated in adverse trends in human reproduction, including infertility and increasing demand for assisted reproduction. Here, we study the action of 96 ubiquitous EDCs on human sperm. We show that structurally diverse EDCs activ...

Indicators of merit for the mass spectrometric results. DOI: http://dx.doi.org/10.7554/eLife.01438.020

Sperm are equipped with a unique set of ion channels that orchestrate fertilization. In mouse sperm, the principal K+ current (IKSper) is carried by the Slo3 channel, which sets the membrane potential (Vm) in a strongly pHi-dependent manner. Here, we show that IKSper in human sperm is activated weakly by pHi and more strongly by Ca2+. Corresponding...

Author Summary New life begins with the fusion of a sperm and an oocyte. During fertilization, sperm cope with demanding endeavors: they have to locate the egg by directed swimming and penetrate the oocyte's vestments. Cyclic nucleotides and their targets represent one of the most ancient signaling systems and are important for the control of sperm...

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The sperm-specific CatSper channel controls the intracellular Ca(2+) concentration ([Ca(2+)](i)) and, thereby, the swimming behaviour of sperm. In humans, CatSper is directly activated by progesterone and prostaglandins-female factors that stimulate Ca(2+) influx. Other factors including neurotransmitters, chemokines, and odorants also affect sperm...

In sea urchin sperm of Arbacia punctulata, a guanylyl cyclase (GC) serves as chemotaxis receptor that enables sperm to respond to a single molecule of the chemoattractant, resact. The efficiency of resact capture is high, because GC covers about 50% of the flagellar surface and binds resact with picomolar affinity. Furthermore, the binding affinity...

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca(2+) increase by a non-genomic mechanism. The Ca(2+) signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm. However, the underlying signalling mechanism has remained mysterious. Here we...

Sperm of the sea urchin Arbacia punctulata can respond to a single molecule of chemoattractant released by an egg. The mechanism underlying this extreme sensitivity is unknown. Crucial signaling events in the response of A. punctulata sperm to chemoattractant include the rapid synthesis of the intracellular messenger guanosine 3',5'-monophosphate (...

The flagellate Euglena gracilis contains a photoactivated adenylyl cyclase (PAC), consisting of the flavoproteins PACa and PACb. Here we report functional expression of PACs in Xenopus laevis oocytes, HEK293 cells and in Drosophila melanogaster, where neuronal expression yields light-induced changes in behavior. The activity of PACs is strongly and...

Eggs attract sperm by chemical factors, a process called chemotaxis. Sperm from marine invertebrates use cGMP signalling to transduce incident chemoattractants into changes in the Ca2+ concentration in the flagellum, which control the swimming behaviour during chemotaxis. The signalling pathway downstream of the synthesis of cGMP by a guanylyl cycl...

In invertebrates, the biogenic-amine octopamine is an important physiological regulator. It controls and modulates neuronal development, circadian rhythm, locomotion, 'fight or flight' responses, as well as learning and memory. Octopamine mediates its effects by activation of different GTP-binding protein (G protein)-coupled receptor types, which i...

Biogenic amines and their receptors regulate and modulate many physiological and behavioural processes in animals. In vertebrates, octopamine is only found in trace amounts and its function as a true neurotransmitter is unclear. In protostomes, however, octopamine can act as neurotransmitter, neuromodulator and neurohormone. In the honeybee, octopa...